Methods for carbonate surface coating and related bone void filler compositions

ABSTRACT

Methods for preparing bone void filler substrates with carbonate surface coatings to promote bone growth.

This application is a divisional of and claims priority to and thebenefit of application Ser. No. 15/812,847 filed Nov. 14, 2017 andissued as U.S. Pat. No. 10,368,995 on Aug. 6, 2019, which claimedpriority to and the benefit of application Ser. No. 62/421,541 filed onNov. 14, 2016—each of which is incorporated herein by reference in itsentirety.

BACKGROUND OF INVENTION

Bone void fillers (BVF) are useful as scaffolds for bone healing. Ascaffold conducts bone growth over gaps too large for bone to bridge byitself, and can accelerate the rate of bone healing in voids of allsizes. Calcium salts are generally recognized as a class of BVFmaterials. For instance, calcium phosphate salts are commonly used asthey are related to hydroxyapatite (HA), which is a form of calciumphosphate in bone material. Calcium sulfate and calcium carbonate, whilenot containing phosphate, are also useful as BVF materials.

The bone healing process consists of three major stages: removal ofdamaged bone debris, growth of new bone, and final bone remodeling.Specialized bone cells called osteoclasts participate in the removal ofbone debris and in resorbing mature bone to aid in remodeling. Othercells called osteoblasts grow new bone onto a collagen structure formedby fibroblasts or onto already existing mineralized surfaces. Thesequence of bone growth and remodeling is controlled by specificproteins of the general class of growth factors.

Successful scaffold materials generally allow direct attachment ofosteoblasts to their surfaces, and the scaffolds are then eventuallyremodeled and finally replaced by bone. However, the remodeling ratemust not be faster than the rate of bone growth or the bone may notheal. Conventional scaffold materials are especially suited tosupporting osteoblast activity and are intended to last until bone hasfully bridged any gaps.

Non-cemented implants intended for use in bone can also benefit from anosteoconductive surface. Such implants include joint prostheses, screws,plates, spinal stabilizing devices, etc. Such metal or polymericimplants (in particular, prostheses) are often coated with HA to providea more bone compatible surface. (Even the metal of such an implant canbe specified to be more bone compatible by, for example, using atitanium alloy instead of a cobalt chrome alloy.) An HA plasma sprayedcoating can facilitate bone on-growth onto the implant with long-termstability occurring as the coating remodels until the bone is attacheddirectly to the implant surface.

Calcium carbonate applied to an HA coating can speed up the naturalremodeling process and achieve final stability sooner than otherwisepossible. This can be an advantage especially in dental applicationswhere a slightly porous HA coating can more easily become infected, ascompared to a coating in a deep internal location such as a hip implant.As a result, rapid remodeling of the HA coating lessens the likelihoodof failure due to infection.

A perceived drawback to use of calcium carbonate is the tendency tostimulate osteoclast activity. This stimulation is probably due to therelatively rapid dissolution of calcium carbonate compared to calciumphosphates and the accompanying release of calcium ions. However, as theactive osteoclasts break down bone they liberate osteoblast stimulatinggrowth factors from the bone and, in doing so, can actually bring aboutmore rapid bone healing. But calcium carbonate is not as effective inlarge voids because it is too soluble. The solubility means calciumcarbonate may not be stable enough to function as a scaffold long enoughfor the bone gap to be bridged. As an alternate approach, calciumcarbonate granules or powder can be mixed with a more stable,conventional BVF material, but the calcium carbonate component of suchmixtures tends to separate and segregate, thereby inducing concerns ofthe sort outlined above.

SUMMARY OF THE INVENTION

In light of the foregoing, it is an object of the present invention toprovide bone void filler compositions and/or methods for theirpreparation, thereby overcoming various deficiencies and shortcomings ofthe prior art, including those outlined above. It will be understood bythose skilled in the art that one or more aspects of this invention canmeet certain objectives, while one or more other aspects can meetcertain other objectives. Each objective may not apply equally, in allits respects, to every aspect of this invention. As such, the followingobjects can be viewed in the alternative with respect to any one aspectof this invention.

It can be an object of the present invention to provide a calciumcarbonate bone void filler composition with sufficient stability topromote growth in a bone tissue gap.

It can be an object of the present invention to provide a scaffoldcomprising such a calcium carbonate composition to conduct andfacilitate bone growth over gaps otherwise too large for proper bonehealing.

It can be an object of the present invention, alone or in conjunctionwith one or more of the preceding objectives, to provide a methodologyfor the preparation of such bone void filler scaffold compositions foruse in bone healing.

Other objects, features, benefits and advantages of the presentinvention will be apparent from this summary and the followingdescriptions of certain embodiments, and will be readily apparent tothose skilled in the art having knowledge of bone growth and healingprocesses and compositions and related methodologies for promoting thesame. Such objects, features, benefits and advantages will be apparentfrom the above as taken into conjunction with the accompanying examples,data and all reasonable inferences to be drawn therefrom.

In part, the present invention can be directed to a method of preparingdiscrete calcium carbonate particles on a substrate surface. Such amethod can comprise providing a carbonatable calcium precursor componentand applying such a precursor component to a bone void filler substrate;and contacting such a substrate with a carbon dioxide source to convertat least a portion of such an applied carbonatable calcium precursorcomponent to calcium carbonate, and provide calcium carbonate particleson such a substrate. In certain embodiments, such a carbonatable calciumprecursor component can be, without limitation, selected from calciumchloride, calcium oxide and calcium acetate. Such a precursor can beapplied by procedures selected from dipping or soaking such a substratein an aqueous solution of such a carbonatable calcium precursorcomponent and spraying such a substrate therewith. Regardless, such acarbon dioxide source can be selected from gaseous carbon dioxide,liquid supercritical carbon dioxide and sodium carbonate. In certainsuch embodiments, contact with carbon dioxide can, optionally, be in thepresence of water, such a water presence as can be selected fromatmospheric water vapor and water applied to such a substrate.

In certain embodiments, such a carbonatable calcium precursor can betreated with an alkali metal hydroxide to provide calcium hydroxide. Incertain such embodiments, such a treatment can be with sodium hydroxide.Carbonation with a carbon dioxide source can then convert calciumhydroxide to calcium carbonate. Regardless, such a bone void fillersubstrate can comprise a material known to those skilled in the art,such a material as can be selected from calcium salts, including but notlimited to calcium phosphates, collagen-based materials and organicbone, polymers, metals and metal alloys and combinations thereof, in aphysical form such as but not limited to particles, blocks,specifically-molded or machined implants, collagen sponges or strips andallograft or xenograft tissues.

In part, the present invention can also be directed to a method ofpreparing a calcium carbonate surface coating. Such a method cancomprise providing a carbonatable calcium precursor component selectedfrom calcium chloride, calcium oxide and calcium acetate, and applyingsuch a precursor component to the surface of a bone void fillersubstrate; and contacting such a substrate with a carbon dioxide source,optionally in the presence of water, to convert at least a portion ofsuch an applied carbonatable calcium precursor component to calciumcarbonate, and provide a coating of dispersed calcium carbonateparticles on such a substrate surface. Such a precursor can be appliedby procedures selected from dipping or soaking such a substrate in anaqueous solution of such a carbonatable calcium precursor component andspraying such a substrate therewith. Regardless, such a carbon dioxidesource can be selected from gaseous carbon dioxide, liquid supercriticalcarbon dioxide and sodium carbonate. In certain such embodiments, such awater presence can be selected from atmospheric water vapor and waterapplied to such a substrate.

In certain embodiments, such a carbonatable calcium precursor can betreated with sodium hydroxide to provide calcium hydroxide. Carbonationwith a carbon dioxide source can then convert calcium hydroxide tocalcium carbonate. Regardless, such a bone void filler substrate cancomprise materials of the sort discussed above or illustrated elsewhereherein.

In part, the present invention can also be directed to a method of usingcomparative calcium salt solubilities to prepare a bone void fillersubstrate comprising calcium particles thereon. Such a method cancomprise providing a calcium salt precursor component having a watersolubility; applying such a precursor component to a bone void fillersubstrate; and treating such an applied precursor component with atransformation component selected from alkali metal hydroxide and alkalimetal carbonate components to provide on such a substrate a calciumcomponent having a water solubility less than the water solubility ofsuch a precursor component, such a calcium component as can be selectedfrom calcium hydroxide and calcium carbonate particles.

Such a precursor component can be selected from calcium chloride,calcium oxide and calcium acetate. In certain embodiments,transformation with an alkali metal carbonate component (e.g., withoutlimitation, sodium carbonate) can provide desired calcium carbonateparticles on such a substrate. In certain other embodiments,transformation with an alkali metal hydroxide component (e.g., withoutlimitation, sodium hydroxide) can provide less water soluble calciumhydroxide particles on such a substrate. In certain such embodiments,subsequent contact of such a substrate with a carbon dioxide source ofthe sort discussed above, optionally in the presence of water, canconvert at least a portion of such calcium hydroxide to calciumcarbonate particles on such a substrate.

Accordingly, the present invention can be, in part, directed to acomposition resulting from the present methodology. Such a compositioncan comprise a biocompatible substrate component and discrete particlesof calcium carbonate thereon. In certain embodiments, such a substratecan be a bone void filler component comprising one or more materials ofthe sort discussed above or illustrated elsewhere herein. In certainsuch embodiments, such calcium carbonate particles can have a micro- ornanocrystalline morphology, such particles as can be on, bound and/orcoupled to a surface of such a substrate component. Regardless, asurface of such a substrate component can be porous, and such calciumcarbonate particles and/or crystals can be present therein. Ascontemplated in conjunction with the methodologies of this invention,such a composition can be employed for application as a bone void fillerscaffold, positioned within or over a gap or void in bone tissue andused to promote bone growth and healing.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

As demonstrated by certain non-limiting embodiments, the presentinvention provides a method to form particles or crystals of calciumcarbonate dispersed about the surface (including inside pores) of abiocompatible BVF substrate, such as but not limited to a bone implant.As such, fabrication is simplified and scaffold effectiveness isincreased because the material is all one phase rather than a mixture ofdifferent materials that may segregate.

The calcium carbonate surface treatment of this invention can be appliedto substrates comprising materials known to those skilled in the art(e.g., without limitation implant materials) such as calcium saltsincluding but not limited to calcium phosphates (e.g., hydroxyapatite),collagen based materials, anorganic bone, allograft bone, polymers, andmetals/alloys. Any such substrate/material coated with precipitatedcalcium carbonate particles/crystals, as described herein, can beconsidered in the context of this invention.

Calcium carbonate has a very low solubility (about 0.013 g/1000 mlwater), and it is impractical to soak a BVF substrate in a calciumcarbonate solution for the purposes of obtaining a coating. A preferredprocess, in accordance with certain non-limiting embodiments of thisinvention, starts with a more soluble calcium compound (salt) that istransformed to a calcium carbonate precipitate on a substrate surface.In accordance with broader aspects of this invention, there are manypossible routes to obtain this result. The choice of what route to useis limited only by the chemical and/or physical properties of a BVFsubstrate to be treated.

EXAMPLES OF THE INVENTION

The following non-limiting examples and data illustrate various aspectsand features relating to the methods/compositions and/or devices of thepresent invention, including the preparation of various substratescomprising calcium carbonate coatings. In comparison with the prior art,the present methods, compositions and/or devices provide results anddata which are surprising, unexpected and contrary thereto. While theutility of this invention is illustrated through the use of severalcarbonatable calcium precursor components, BVF substrates and reagentswhich can be used therewith, it will be understood by those skilled inthe art that comparable results are obtainable with various otherprecursor components, BVF substrates and reagents, as are commensuratewith the scope of this invention.

Example 1a

With reference to the equations, below, one approach involves soaking,spraying, or dipping a bone void filler material/substrate in a calciumchloride solution; and soaking dipping, or spraying the calcium chloridewetted substrate with a sodium hydroxide solution to transform thecalcium chloride to relatively insoluble calcium hydroxide (and solublesodium chloride, NaCl). The treated substrate can then be dried(optional) and rinsed with water to remove the NaCl. The final step isto expose the sodium hydroxide treated substrate to a carbon dioxide(CO₂) source to transform the hydroxide into carbonate. Alternatively,such a washing step to remove NaCl can be carried out after carbonatetransformation. An advantage is that the carbonate is less soluble thanthe hydroxide, and such an alternative can provide more carbonate on thebone void filler substrate.

Calcium hydroxide has a higher solubility than calcium carbonate, but itis still very low (about 1.8 g/1000 ml water). Calcium chloride has asolubility of about 740 g/1000 ml water which is over 400 times greaterthan that of calcium hydroxide and so provides a better route thandirect treatment with calcium hydroxide to cover the substrate surfacewith a calcium salt. Sodium hydroxide has a very high water solubility(about 1100 g/1000 cc water), and can be used very sparingly totransform a calcium chloride coated substrate to a calcium hydroxideprecipitate coating without washing away much of the calcium chloride.The transformation to carbonate is preferably done by exposure togaseous CO₂, although liquid supercritical CO₂ can be used. The surfaceof the substrate to be treated is preferably damp, or water vapor can beintroduced with the CO₂ to provide a humid conversion atmosphere.

The end result is a dispersion of nano-sized calcium carbonate crystalsover the BVF substrate surface. The surface architecture is unique andcannot be duplicated by depositing a pre-formed calcium carbonatematerial on the device surface.Calcium chloride+sodium hydroxide→calcium hydroxide+saltCaCl₂(aq)+NaOH(aq)→Ca(OH)₂(s)+2NaCl(aq)Calcium hydroxide+carbon dioxide→calcium carbonate+waterCa(OH)₂(s)+CO₂(g)→CaCO₃(s)+H₂O(aq)

Example 1b

With reference to the preceding, an alternative route uses an organiccalcium salt such as calcium acetate (solubility is about 340 g/1000 mlwater), followed by treatment with sodium hydroxide to obtain calciumhydroxide and sodium acetate. Carbonation, as described above, providesthe desired calcium carbonate particles/crystals.

Example 2

Another approach is to cover a BVF substrate surface with calciumacetate (by soaking, dipping, or spraying a calcium acetate solution),then treating the substrate with a sodium carbonate solution (solubilityabout 340 g/1000 cc water) to transform the calcium acetate to calciumcarbonate and soluble sodium acetate that can be rinsed away.calcium acetate+sodium carbonate→calcium carbonate+sodium acetateCa(C₂H₃O₂)₂(aq)+Na₂CO₃(aq)→CaCO₃(s)+2NaC₂H₃O₂(aq)

Example 3

Another approach is to cover a BVF substrate surface with calciumchloride (by soaking, dipping, or spraying a calcium chloride solution),then treating the substrate with a sodium carbonate solution totransform the calcium chloride to calcium carbonate along with theformation of soluble sodium chloride that can be rinsed away.Calcium chloride+sodium carbonate→calcium carbonate+sodium chlorideCaCl₂(aq)+Na₂CO₃(aq)→CaCO₃(s)+2NaCl(aq)

Example 4

Another approach is to transform calcium oxide or another suchcarbonatable precursor component present in/on a corresponding BVFsubstrate to calcium carbonate by an aqueous reaction with sodiumcarbonate. Such a transformation may be a two-step reaction where thecalcium oxide is first transformed to calcium hydroxide which thenreacts with the sodium carbonate to produce calcium carbonate and sodiumhydroxide. The sodium hydroxide is very water soluble and can be rinsedaway.Calcium oxide in water→calcium hydroxideCaO(s)+H₂O→Ca(OH)₂(s)Calcium hydroxide+sodium carbonate→calcium carbonate+sodium hydroxideCa(OH)₂(s)+Na₂CO₃(aq)→CaCO₃(s)+2NaOH(aq)

Overall reaction:Calcium oxide+sodium carbonate→calcium carbonate+sodium chlorideCaO(aq)+H₂O+Na₂CO₃(aq)→CaCO₃(s)+2NaOH(aq)

While the principles of this invention have been described inconjunction with certain embodiments, it should be understood clearlythat these descriptions are provided only by way of example and are notintended to limit, in any way, the scope of this invention. Forinstance, in conjunction with comparative carbonate salt solubilities, atransformation component such as an alkali metal hydroxide or carbonatecan have a solubility greater than that of a carbonatable calciumprecursor component. Likewise, methods and resulting compositions of thepresent invention can be considered in conjunction with various boneimplant materials known to those skilled in the art, including but notlimited to a mammalian biocompatible anorganic bone mineral matrixproduced by removal of organic components. Alternatively, suchsubstrates can be autologous bone from an implant recipient or allograftbone, such as that obtained from a bone bank. Other advantages andfeatures will become apparent from the claims hereinafter, with thescope of such claims determined by reasonable equivalents as would beunderstood by those skilled in the art and made aware of this invention.

I claim:
 1. A method of preparing a bone void filler substratecomprising calcium component particles thereon, said method comprising:providing a carbonatable calcium salt precursor component having a watersolubility; applying said precursor component to a bone void fillersubstrate; and treating said applied precursor component with atransformation component selected from alkali metal hydroxide and alkalimetal carbonate to provide on said substrate a calcium component havinga water solubility less than the water solubility of said precursorcomponent, said calcium component selected from calcium hydroxide andcalcium carbonate particles.
 2. The method of claim 1 wherein saidcalcium salt precursor component is selected from calcium chloride,calcium oxide and calcium acetate.
 3. The method of claim 1 wherein saidtransformation component is selected from sodium hydroxide and sodiumcarbonate.
 4. The method of claim 1 wherein said calcium component iscalcium hydroxide, and said transformation component is sodiumhydroxide.
 5. The method of claim 4, further comprising contacting saidsubstrate with a carbon dioxide source to provide calcium carbonateparticles thereon.
 6. The method of claim 5 wherein said carbon dioxidesource, optionally in the presence of water, is selected from gaseouscarbon dioxide, liquid supercritical carbon dioxide and sodiumcarbonate.
 7. The method of claim 6 wherein the presence of water isselected from atmospheric water vapor about said substrate and waterapplied to said substrate.
 8. The method of claim 1 wherein said bonevoid filler substrate comprises a material selected from calcium salts,collagen, natural mammalian bone, polymers, metals and combinationsthereof.
 9. The method of claim 1 wherein said carbonatable calciumprecursor component is provided as an aqueous solution thereof, andapplication of said carbonatable calcium precursor component is selectedfrom dipping, soaking and spraying said substrate therewith.
 10. Themethod of claim 1 wherein said substrate is applied to a mammalian bonevoid.